The long-term research goal of this proposal is to understand the molecular mechanisms that are involved in the development of "mucocillary differentiation" of airway epithelium. These mucociliary function play important roles in lung diseases and pulmonary defense. However, the molecular mechanism involved in the regulation of mucociliary differentiation has not been elucidated. The overall hypothesis of the proposal is to test if the expression of mucociliary differentiation is regulated by various vitamin A-responsive genes. To address this hypothesis, qa well-defined vitamin A-dependent mucous cell differentiation system of human/monkey tracheobronchial epithelial (TBE) cell culture will be used to elucidate the roles of various vitamin A- responsive genes, especially the earliest ones, in the regulation. Specifically, the research designs and aims are: 1) isolate and characterize early vitamin A-responsive genes involved in airway mucous cell differentiation to confirm the hypothesis that change in gene expression at the mRNA level is associated with the early event of vitamin A-induced mucous cell differentiation. 2) Elucidate the mechanism of vitamin A in regulating t he expression of these early genes to test the hypothesis that change in gene expression, especially at the early period, occurs at the transcriptional level. 3) Elucidate the roles of these early vitamin A-responsive genes in the regulation of vitamin A-induced mucous cell-differentiation to support the hypothesis that these early genes are involved in the initiation of mucous cell differentiation induced by vitamin A.